In this U34 application, we propose to have a 2 year planning period that will allow us to prepare for conducting a clinical study evaluating the efficacy of the use of propranolol for enhancing the benefit of activating rehabilitation for treatng fibromyalgia syndrome (FMS). FMS is a common chronic pain disorder with no cure. Literature indicates that no single modality is universally effective and the best evidence recommends the use of multimodal approach including activating exercise, cognitive behavioral therapy, and education. Furthermore, research has yielded that FMS patients experience adrenergic dysfunction, especially in response to exercise, and re-regulation of this may be very important for successful treatment. However, post exertion pain and fatigue, particularly delayed onset muscle soreness (DOMS), are very common in FMS, making it difficult for patients to comply with rehabilitative regimen. Our preliminary work suggests that 1) low dose propranolol helps restore the adrenergic response in FMS patients, 2) low dose propranolol reduces clinical pain in FMS patients, 3) activating rehabilitation can improve FMS symptoms, and 4) propranolol may improve DOMS. Furthermore, in our previous work with sensory, adrenergic and immune gene expression, we have shown that those expression profiles in response to exercise greatly differ between FMS and healthy people. Thus, we hypothesize that propranolol may help pain in FMS and DOMS, thereby enhancing the effect of rehabilitative effort, and the effects should be reflected in the changes in the gene expression profiles. In this proposed study, we will recruit 200 FMS women with a history of DOMS, who will be randomly assigned to either low dose propranolol with rehabilitation or placebo with rehabilitation. We will perform a series of gene expression analyses to track the changes. We aim to 1) examine the enhancing effect of propranolol on the benefit of multimodal rehabilitation for treating FMS, and 2) evaluate and quantify the role of the gene expression profiles in response to propranolol and activating rehabilitation for FMS patients. During the planning stage, we will 1) conduct feasibility analyses for patient recruitment, 2) refine the study protocol, 3) develop recruitment strategies particulary to increase participants from the ethnic minority groups, 4) develop the Manual of Operating Procedures and complete regulatory activities, 5) develop database and refinement of the analytical procedures, 6) refine the safety monitoring and establish an external safety monitoring board, 7) develop a training manual for study clinicians, and 8) prepare a U01 application.